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WO1996031227A1 - Phosphonates, biphosphonates et preparations pharmaceutiques les contenant - Google Patents

Phosphonates, biphosphonates et preparations pharmaceutiques les contenant Download PDF

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Publication number
WO1996031227A1
WO1996031227A1 PCT/US1996/004810 US9604810W WO9631227A1 WO 1996031227 A1 WO1996031227 A1 WO 1996031227A1 US 9604810 W US9604810 W US 9604810W WO 9631227 A1 WO9631227 A1 WO 9631227A1
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WO
WIPO (PCT)
Prior art keywords
zero
integer
compound
designates
amino acid
Prior art date
Application number
PCT/US1996/004810
Other languages
English (en)
Inventor
Eli Breuer
Gershon Golomb
Gordon L. Amidon
Ivan Sergeievitch Alferiev
Naama El-Hanany Rozen
Aviva Friedman-Ezra
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority to US08/930,676 priority Critical patent/US6541454B1/en
Priority to AU54461/96A priority patent/AU5446196A/en
Publication of WO1996031227A1 publication Critical patent/WO1996031227A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Calcium-related disorders in general and osteoporosis in particular are a major public health problem in developed countries.
  • Several important pathological conditions are calcium-related and involve irregularities in calcium
  • Bisphosphonates are a relatively new family of drugs used clinically in various calcium-related disorders including tumor osleolysis, and are undergoing clinical trials for osteoporosis. They are poorly absorbed following oral
  • peptidyl compounds will have better activity on bone: In particular, they can be used in cases where the formation and breakdown of bone is disturbed, for example in cases of osteoporosis''. None is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration.
  • the dosage is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration.
  • the dosage range recommended (see column 6 ) is from ."1 mg to 1000 mg, and preferably from 10 to 200 mg.” Such doses are typical for non-absorbable bisphosphonates such as etidronate and pamidronate.
  • the daily oral recommended dose of a recently approved bisphosphonate in the US, alendronate (Fosamax) is 10 mg and 40 mg, in the
  • Bisphosphonates have been approved for clinical use in Paget's disease, tumor osteolysis, and hypercalcemia of malignancy and approved in some countries for
  • the treatment protocol of pamidronate in tumor osteolyis is 1-day slow and diluted IV infusion to avoid thrombophlebitis, but treatment is repeated if norniocalcemia is not attained.
  • Another example is the chronic therapy (years) required in osteoporosis.
  • Drugs require a degree of lipophilicity to pass through the GI barrier.
  • nonpolar prodrugs are often utilized. Due to the wide variety of esterases present in the target tissue for oral prodrug- regeneration, esters are the most common prodrugs when GI absorption is considered. Acyloxymethyl esters of bisphosphonic acids were proposed however this
  • bioavailability can be achieved due to the recognition by the active carrier transporter of the intestinal mucosae and the hydrolysis to the parent drug following oral administration.
  • the prodrug in our invention is a delivery system rather than a new compound for bone diseases. Therefore, our selection of new compounds is based on enhanced absorption for the GI tract and hydrolysis to the parent compound resulting in improved oral, clinical treatment by a low dose.
  • the selection of the di/tri-peptidyl moiety is based on transporter recognition and hydrolysis and not, as in Bosies et al patent, on resorbing activity on the bone.
  • the present invention relates to novel compounds of the general formula
  • Z 1 and Z 2 are a side chain of an amino acid or hydrogen, when one or both of Z 1 and Z 2 are a
  • Z is -OH , where Q is
  • Z 3 is a bond or a spacer group selected from NH, CO, NHCO, NHCO(CH 2 ) q -CO, (CH 2 ) r CO where r is zero or an integer, and where q is and integer or zero, m is 2, 3 or 4 ,
  • n is zero an integer
  • X is -H or -OH
  • Y is -H or -NR 2 R 3 ,
  • A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds
  • R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di) alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents, and to pharmaceutical compositions of improved absorption from the gastro-intestinal tract which contain as active ingredient an efficient quantity of a compound defined above.
  • n designates zero or an integer
  • n designates 2, 3 or 4;
  • R 1 and R 2 which may be identical or different, each designates a side chain of an amino acid.
  • the compounds defined above are aminoacyl derivatives when n is zero, and they are peptidyl-bisphosphonates when n is an integer as defined above.
  • amino acids can be used, and preferred ones for use in the peptidyl chain according to the invention are: proline
  • the invention furthermore relates to a method for the production of derivatives defined above, or their salts which comprises linking a desired bisphosphonate
  • the invention further relates to pharmaceutical
  • compositions, for oral administration which contain an effective quantity of a novel derivative defined above.
  • the compositions according to the present invention are characterized by high absorption from the gastrointestinal tract.
  • the dosage in humans is dependent on various factors including drug potency, age, disease type and state, and the mode of administration. Since our invention provides significantly enhanced oral absorption the dosage should be determined according to the extent of absorption of a specific peptidyl-bisphosphonate derivative. Therefore, the dose of the prodrug is typically about 20 to 100 times lower than the one usually prescribed for oral administration. One should also recall that the MW of a prodrug is higher than the active drug.
  • the effective dosage range is form about 0.001 mg to about 100 mg per patient per day, a preferred range being of the order of about 0.02 mg to 1 mg per patient, per day in oral administration.
  • novel compounds are effectively absorbed and after being absorbed, and due to enzymatic action, decomposed to provide the free active drug. It is preferred to use such peptidyl chains which are effective in balancing the negative charges of the bisphosphonates. It is possible that some of the novel conjugates are effective as such in the human body.
  • Peptidyl prodrugs of clinically approved bisphosphonates are effectively absorbed following oral administration.
  • the present prodrug strategy was based on the rationale of neutralizing the negatively charged bisphosphonate molecule by a positively charged amino acid, and or at the same time making use of the peptide carrier system serving as a transporter for the prodrug.
  • the prodrug is subsequently hydrolyzed by a mucosal cell cytosolic enzyme such as prolidase, prolinase, dipeptidase, aminotripeptidase or possibly other hepatic/plasma enzymes, or is effective as such.
  • a mucosal cell cytosolic enzyme such as prolidase, prolinase, dipeptidase, aminotripeptidase or possibly other hepatic/plasma enzymes, or is effective as such.
  • a peptidylbisphosphonate can be recognized by the nonspecific peptide transporter
  • the free amino groups on the amino acid side chain are expected to neutralize partially or fully the phosphonate negative charges.
  • Amino acids and peptides were linked to geminal-aminoalkylidenebisphosphonates (for example Pamidronate and Alendronate) by a simple chemical
  • Aminoacyl or peptidyl bisphosphonates thus obtained are reconverted to the parent drug by enzymes or alternatively may be active as such in bone diseases.
  • the Figures relate to the concentration of Phe-Pamidronate and Pamidronate in various organs 24 hours after Peroral Administration in rats, (Pro-( 3 H)Phe-( 14 C) Pam, ( 14 C) Pam, 10 mg / kg.
  • the scale indicates % of total dose.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur de nouveaux dérivés de certains phosphonates et bisphosphonates et spécialement sur des composés du type pamidronate ou alendronate et plus particulièrement sur les dérivés amonoacyle et peptidyle desdits composés. L'invention porte en outre sur des préparations pharmaceutiques contenant comme principe actif les quantités requises desdits composés, et qui sont caractérisées par une bonne absorption par le corps humain après ingestion.
PCT/US1996/004810 1995-04-04 1996-04-03 Phosphonates, biphosphonates et preparations pharmaceutiques les contenant WO1996031227A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/930,676 US6541454B1 (en) 1995-04-04 1996-04-03 Phosphonates, biphosphonates and pharmaceutical compositions containing them
AU54461/96A AU5446196A (en) 1995-04-04 1996-04-03 Phosphonates, biphosphonates and pharmaceutical compositions containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL11324695A IL113246A (en) 1995-04-04 1995-04-04 Bisphosphonates and pharmaceutical compositions containing them
IL113246 1995-04-04

Publications (1)

Publication Number Publication Date
WO1996031227A1 true WO1996031227A1 (fr) 1996-10-10

Family

ID=11067315

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/004810 WO1996031227A1 (fr) 1995-04-04 1996-04-03 Phosphonates, biphosphonates et preparations pharmaceutiques les contenant

Country Status (3)

Country Link
AU (1) AU5446196A (fr)
IL (1) IL113246A (fr)
WO (1) WO1996031227A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432931B1 (en) 1998-06-24 2002-08-13 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
WO2022159492A1 (fr) * 2021-01-19 2022-07-28 William Marsh Rice University Administration de polypeptides spécifique des os

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364846A (en) * 1991-07-12 1994-11-15 Hoechst Aktiengesellschaft N-cycloalkylaminoethane-1,1-bis (phosphonic acid) useful for the treatment of osteoporosis and degenerative joint disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364846A (en) * 1991-07-12 1994-11-15 Hoechst Aktiengesellschaft N-cycloalkylaminoethane-1,1-bis (phosphonic acid) useful for the treatment of osteoporosis and degenerative joint disease

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
US6974802B2 (en) 1998-02-13 2005-12-13 Medivir Ab Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine
US7071173B2 (en) 1998-02-13 2006-07-04 Medivir Ab Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
US6432931B1 (en) 1998-06-24 2002-08-13 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US6699850B2 (en) 1998-06-24 2004-03-02 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
WO2022159492A1 (fr) * 2021-01-19 2022-07-28 William Marsh Rice University Administration de polypeptides spécifique des os

Also Published As

Publication number Publication date
IL113246A0 (en) 1995-07-31
IL113246A (en) 2004-08-31
AU5446196A (en) 1996-10-23

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